Safety and efficacy of the EZH1/2 inhibitor valemetostat tosylate (DS-3201b) in pediatric patients with malignant solid tumors (NCCH1904): A multicenter phase I trial
Abstract
10003
Background:
Valemetostat tosylate (DS-3201b; valemetostat) is a first-in-class dual inhibitor targeting the epigenetic regulators EZH1 and EZH2. In Japan, valemetostat has been approved for the treatment of r/r adult T-cell leukemia/lymphoma and peripheral T-cell lymphoma. These enzymes are implicated in tumors characterized by SMARCB1/INI1 deficiencies, such as malignant rhabdoid tumors or epithelioid sarcoma, which frequently occur during childhood and adolescence. Valemetostat is expected to show antitumor activity against such malignancies.
Methods:
This open-label, multicenter phase I trial evaluated the safety, efficacy, and recommended phase 2 dose (RP2D) of valemetostat in pediatric patients with malignant solid tumors. Valemetostat was administered orally once daily in 28-day cycles. The dose-escalation phase used a 3 + 3 design, testing three dose levels (150, 200, and 250 mg/1.7 m
2
). Following RP2D determination, 15 patients were enrolled in the expansion cohort. The primary endpoint was dose-limiting toxicity (DLT) incidence in the dose-escalation cohort.
Results:
Between March 2020 and January 2023, 30 pediatric patients were enrolled (median age: 8 yr; range: 3–19 yr). Among these, 13 (43.3%) patients were INI1-negative by immunohistochemistry. Diagnoses included atypical teratoid/rhabdoid tumor (AT/RT,
n
= 6), malignant rhabdoid tumor (
n
= 1), neuroblastoma (NB,
n
= 8), and chordoma (
n
= 3). No DLTs were observed among 12 evaluable patients, and 250…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 15 participants or records.
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